Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling

Francesca Nazio,Francesca Diomedi Camassei,Sara Marinelli,Maria Vinci,Evelina Miele,Ignazio Caruana,Elena Papaleo,Giacomo Milletti,Luca Compagnucci ,Enrico Velardi,Agnese Pò ,Luca Tiberi,Marco Pezzullo,Claudio Ballabio,Sofia Reddel,Matteo Gianesello,Antonella Cacchione,Concetta Quintarelli,Andrea Carai,Biagio De Angelis,Donatella Ceglie,Angela Mastronuzzi,Simona Caruso,Franco Locatelli,Antonio Camera,Matteo Bordi,Caterina Ferraina,Elisabetta Ferretti,Luana Abballe,Silvia Campello,Francesco Cecconi

doi:10.1007/s00401-021-02347-7

Abstract

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.

Highlights

Medulloblastoma (MB) is the most common malignant paediatric brain tumour localized in the hindbrain
We show that AMBRA1 is differentially expressed in MB subtypes, depending on c-MYC and Myc-Interacting Zinc Finger Protein 1 (MIZ-1) expression
AMBRA1 is known to be crucial for both nervous system development and autophagy

Summary

Introduction

Medulloblastoma (MB) is the most common malignant paediatric brain tumour localized in the hindbrain. Using multiple complementary bioinformatic approaches, a study refined Group 3/4 classification, identifying eight subtypes (I–VIII), and describing a more complex intratumoral heterogeneity within Group 3 and 4 [39, 84]. A large body of evidence reveals that key properties related to MB aggressiveness are: stemness, invasion capacity, and cell motility [40]. All these features have been associated with the presence of cancer stem cells (CSCs) in MB [87, 88]. Several roles for AMBRA1 and autophagy have been described in human cancer; its function in the origin of brain tumours, such as MB, and in lineage-specific mechanisms that could regulate stem cell behaviour is largely unknown

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